Influence on the manufacturing process

Chapter VI ǀ Lipids as innovative excipients

134

135

Figure 82 ǀ Influence of the temperature on the maximum piston force during the extrusion (standard program) of formulations consisting of RG 502 H, 20% of oxybutynin hydrochloride, and different fractions of Dynacet 211 P (mean ± standard deviation, n = 2).

Figure 83 ǀ Glass transition temperature of RG 502 H in implants consisting of 80% of the polymer and 20% of oxybutynin hydrochloride or 70% of the polymer, 20% of oxybutynin hydrochloride, and 10% of Dynacet 211 P (mean ± standard deviation, n = 3).

0 5 10 15 20

35 40

45 50

55 60

65 70

75 80

maximum piston force [kN]

extrusion temperature [°C]

no lipid 5% 10% 15% 20%

20 22 24 26 28 30 32

no lipid Dynacet 211 P

glass transition temperature [°C]

Chapter VI ǀ Lipids as innovative excipients

136

acetylated glyceride acts as a plasticizer for the polymer. Especially higher concentrations of the lipid were shown to decrease the implant stability. This is due to the fact that the Tg of RG 502 H is then in the range of the room temperature or even below. Thus, it was decided to store all extrudates at 2 °C to 8 °C.

The implant diameters that were obtained for the different formulations are displayed in Figure 84.

As soon as only 5% of Dynacet 211 P are added, the diameter decreases considerably. Extrusion at 75 °C leads to a value of 1.17 mm ± 0.03 mm while 1.27 ± 0.03 mm can be detected for the lipid-free formulation. With increasing amount of the lipid, this effect becomes less pronounced. Hence, a thickness of 1.11 mm ± 0.05 mm is found for the 20% formulation. Similar to the curves of the maximum piston force, the implant diameters increase until a temperature of 60 °C is reached. The following plateau phase is reflected by slightly decreasing values. Thereafter, both the maximum piston forces and the diameters increase again. However, temperatures lower than 50 °C induce decreasing values for the formulation containing 20% of the acetylated glyceride. It might be speculated that this is closely linked to the melting behavior of the lipid which is characterized by a Tm of 41 °C to 47 °C ( III, 1.3.4). So, it can be assumed that the excipient remains (at least partially) solid at 45 °C and 40 °C.

Figure 84 ǀ Influence of the temperature on the implant diameter. The implants consisted of RG 502 H, 20% of oxybutynin hydrochloride, and different fractions of Dynacet 211 P. Extrusion was performed using the standard program (mean ± standard deviation, n = 2).

Next, the fluctuations of the implant diameters were investigated using the example of the 20%

formulation again ( Figure 85). Apparently, the standard deviations can substantially be optimized 0,9 1,0 1,1 1,2 1,3

35 40

45 50

55 60

65 70

75 80

diameter [mm]

extrusion temperature [°C]

no lipid 5% 10% 15% 20%

137 when the extrusion temperature is reduced. At 40 °C, thinning of the strand is completely avoided ( IV, 1.1), thus resulting in a constant thickness of 1.18 mm ± 0.00 mm. For the temperatures in between 65 °C and 45 °C, similar standard deviations were obtained with 0.01 mm and 0.02 mm. In this range, a clear trend cannot be observed which might be ascribed to the low number of experiments. However, if the extrusion at 75 °C is compared to the one at 40 °C, a tremendous difference shows up. In former case, a zigzag curve is monitored for the implant diameters whereas the latter leads to a straight line.

Figure 85 ǀ Influence of the temperature on the implant diameter. The implants consisted of 60% of RG 502 H, 20% of oxybutynin hydrochloride, and 20% of Dynacet 211 P. Extrusion was performed using the standard program (n = 1).

In addition, the influence of Dynacet 211 P on the reduction of the fill levels during the first extrusion phases was studied. The results are presented in Figure 86. If increasing amounts of the lipid are added, thereby replacing the polymer, two effects can be noticed: on the one hand, the fill levels inside the barrel increase during the compression phase, and on the other hand, they decrease during the heating phases. The latter can be explained by the fact that the amount of RG 502 H which is responsible for the loss of volume is reduced ( IV, 1.1). As a consequence, the fill level reduction declines almost linearly from initially 33.0% for the lipid-free formulation to 3.4% for the 20%

formulation. For comparison purposes, lipid-based implants without poly(lactide-co-glycolide) were 1.10 mm ± 0.04 mm

1.17 mm ± 0.01 mm 1.15 mm ± 0.02 mm

1.22 mm ± 0.01 mm 1.19 mm ± 0.02 mm 1.22 mm ± 0.02 mm 1.20 mm ± 0.01 mm 1.18 mm ± 0.00 mm 1,1

1,2 1,3 1,4 1,5 1,6 1,7 1,8 1,9

0 50 100 150 200 250 300 350 400 450

diameter [mm]

time [s]

75 °C 70 °C 65 °C 60 °C 55 °C 50 °C 45 °C 40 °C

Chapter VI ǀ Lipids as innovative excipients

138

prepared. Independent of the formulation, the fill levels remained unchanged during the heating phases. In contrast, during the compression phase that is run at room temperature, comparatively high values were obtained for the fill level reduction. This means that the lipids are more compressible than the polymer, providing that both materials are solid. As soon as the lipidic excipient is molten, it cannot be further compressed. Coming back to Figure 86, this is the reason why the fill level reduction increases during the compression phase with increasing amounts of Dynacet 211 P. Regarding the overall fill level reduction which includes the first three extrusion phases, it becomes apparent that the values substantially decrease with increasing fractions of the lipid (data not shown). This indicates that the percentage effect of the polymer is much higher than the one of the lipid.

Figure 86 ǀ Influence of the fraction of Dynacet 211 P on the fill level reduction during the extrusion (standard program at 75 °C) of formulations consisting of RG 502 H, 20% of oxybutynin hydrochloride, and different fractions of the lipid (mean ± standard deviation, n = 2).

Aside from the hydrochloride-containing implants, base-containing implants were additionally prepared and analyzed. The minimum extrusion temperature was only determined for the formulation with 10% of the acetylated glyceride and turned out to be 55 °C. This is the same value that was already obtained for the hydrochloride. Concerning the optimization of the extrusion process towards lower temperatures, the base proved to be no longer superior to the salt (considerable differences were found in the absence of the lipid) ( V, 1.1). The corresponding maximum piston force was determined to be 11 kN ± 1 kN, and the implant diameter was 1.28 mm ± 0.05 mm. The standard deviation of the latter points to phase separation processes which

0 5 10 15 20 25 30 35

0 5 10 15 20

fill level reduction [%]

fraction of Dynacet 211 P [%]

compression first and second heating phase

139 were confirmed by the results of the homogeneity tests. As can be seen in Figure 87, the recovery of the base strongly fluctuates around the 100% value. Implants with 93.2% of the intended drug loading as well as implants with 114.8% originate from one and the same batch. In contrast, the recovery of the hydrochloride is very good with 100.3% ± 0.6%. It can be assumed that this API is homogeneously distributed in the polymer matrix.

Figure 87 ǀ Homogeneity of implants consisting of 70% of RG 502 H, 20% of oxybutynin hydrochloride or oxybutynin base, and 10% of Dynacet 211 P. Extrusion was performed using the standard program at 55 °C (n = 6).